The population of age 65 and older is expected to grow by 49% to 55 million by 2020 in the US. Despite advances in the management of sepsis, a large number of such patients die of septic shock and multiple organ failure. Sepsis is particularly a serious problem in the geriatric population since elderly patients with sepsis have a much higher mortality rate. We have shown that an increase in proinflammatory cytokines is greater in aged rats with endotoxemia, resulting in high lethality. We discovered that age-related hyperinflammation is associated with central hyporesponsiveness to a novel "gut-brain" peptide ghrelin, reducing parasympathostimulatory neuronal activity in the dorsal vagal complex of the brain stem. This central (brain) hyporesponsiveness is caused by ghrelin receptor downregulation. Administration of a specific ghrelin receptor antagonist further increases cytokines and worsens tissue injury in young rats with endotoxemia. We also showed that plasma ghrelin is reduced to a much greater extent in aged rats with endotoxemia. A low dose of growth hormone (GH) upregulates ghrelin receptor in aged rats, suggesting that GH is a ghrelinsensitizing agent. Treatment with ghrelin and GH reduces cytokine release and attenuates tissue injury in aged rats. The action of ghrelin is mediated by the vagus nerve, as vagotomy prevents its beneficial effects. We therefore hypothesize that the reduced central responsiveness to ghrelin due to decreased GH, plays a major role in producing the hyperinflammatory state (upregulated TNF, IL-1, IL-6, HMGB-1), resulting in severe organ injury and high mortality after endotoxemia and sepsis in aged animals. We further hypothesize that the beneficial effects of ghrelin and GH in aged septic animals are due to activation of the vagus nerve via a central mechanism. The proposed studies will 1) confirm the role of central ghrelin hyporesponsiveness in mediating endotoxemia-induced hyperinflammation in aging;2) determine whether decreased levels of GH are responsible for the central ghrelin hyporesponsiveness;3) determine whether administration of ghrelin and GH has any beneficial effects in sepsis;and 4) elucidate the mechanisms responsible for the beneficial effect of ghrelin and GH in aged septic animals. The proposed studies will provide novel information about mechanisms responsible for aging-related hyperinflammatory response and organ injury in sepsis and septic shock, and identify new therapeutic approaches to reduce sepsis-induced lethality in the geriatric population.